AAV Gene Therapy Strategies for Lysosomal Storage Disorders with Central Nervous System Involvement - Gene Delivery and Therapy for Neurological Disorders - page 265

Chapter 11

AAV Gene Therapy Strategies for Lysosomal Storage
Disorders with Central Nervous System Involvement

Diane Golebiowski , Allison M. Bradbury , Churl-Su Kwon ,
Imramsjah M. J. van der Bom , Lorelei Stoica , Aime K. Johnson ,
Diane U. Wilson , Heather L. Gray-Edwards , Judith A. Hudson ,
Jacob A. Johnson , Ashley N. Randle , Brian K. Whitlock , James L. Sartin ,
Anna Luisa Kühn , Matthew Gounis , Wael Asaad , Douglas R. Martin ,
and Miguel Sena-Esteves

Abstract

Gene therapy is one of the most promising approaches for the treatment of lysosomal storage disorders
(LSDs). This is especially true for the 75 % of LSDs that have central nervous system (CNS) involvement,
where enzyme replacement therapy (ERT), the standard of care for LSDs, is ineffective in treating the
neurological features of these diseases. Recombinant adeno-associated virus (AAV) vectors have emerged
as the most effi cient and promising gene transfer vehicles for the CNS and in particular for LSDs. Direct
infusion of AAV vectors into interconnected structures in the brain has achieved widespread distribution
of vector and therapeutic levels of lysosomal enzymes throughout the CNS. Early stages of clinical trials
are currently underway for treating neurological disorders with AAV vectors, with much anticipation for
moving these treatments forward to aid patients and families affected by these terrible diseases. In this
chapter, we will detail the protocols used for stereotaxic AAV infusion into the brain of mice, cats, sheep,
and nonhuman primates.

Key words Gene therapy, Lysosomal storage disorders, Stereotaxic brain injections, Mouse, Cat,
Sheep, Nonhuman primate

1 Introduction

Lysosomal storage disorders (LSDs) are caused by a defective
enzyme or cofactor that performs its function ultimately in the lyso-
some. Over 40 lysosomal enzymes work in tandem to break specifi c
covalent bonds sequentially and degrade cellular metabolites to
their basic components (amino acids, lipids, and sugars). A lyso-
somal enzyme defect blocks one or multiple metabolic pathways,
leading to accumulation of specifi c substrates such as glycogen,